Prospective, randomized, controlled trial assessing the effects of a driving pressure-limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan.

BACKGROUND: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. OBJECTIVE: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. METHODS: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. OUTCOMES: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. CONCLUSION: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

Prospective, randomized, controlled trial assessing the effects of a driving pressure-limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan / Estudo randomizado prospectivo e controlado de avaliação dos efeitos de uma estratégia de limitação da driving pressure em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade (estudo STAMINA): protocolo e plano de análise estatística

ABSTRACT Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

RESUMO Contexto: Em estudos observacionais sobre a síndrome do desconforto respiratório agudo, sugeriu-se que a driving pressure é o principal fator de lesão pulmonar induzida por ventilador e de mortalidade. Não está claro se uma estratégia de limitação da driving pressure pode melhorar os desfechos clínicos. Objetivo: Descrever o protocolo e o plano de análise estatística que serão usados para testar se uma estratégia de limitação da driving pressure envolvendo a titulação da pressão positiva expiratória final de acordo com a melhor complacência respiratória e a redução do volume corrente é superior a uma estratégia padrão envolvendo o uso da tabela de pressão positiva expiratória final baixa do protocolo ARDSNet, em termos de aumento do número de dias sem ventilador em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade. Métodos: O estudo STAMINA (ventilator STrAtegy for coMmunIty acquired pNeumoniA) é randomizado, multicêntrico e aberto e compara uma estratégia de limitação da driving pressure com a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet em pacientes com síndrome do desconforto respiratório agudo moderada a grave devido à pneumonia adquirida na comunidade internados em unidades de terapia intensiva. Esperamos recrutar 500 pacientes de 20 unidades de terapia intensiva brasileiras e duas colombianas. Eles serão randomizados para um grupo da estratégia de limitação da driving pressure ou para um grupo de estratégia padrão usando a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet. No grupo da estratégia de limitação da driving pressure, a pressão positiva expiratória final será titulada de acordo com a melhor complacência do sistema respiratório. Desfechos: O desfecho primário é o número de dias sem ventilador em 28 dias. Os desfechos secundários são a mortalidade hospitalar e na unidade de terapia intensiva e a necessidade de terapias de resgate, como suporte de vida extracorpóreo, manobras de recrutamento e óxido nítrico inalado. Conclusão: O STAMINA foi projetado para fornecer evidências sobre se uma estratégia de limitação da driving pressure é superior à estratégia da tabela de pressão positiva expiratória final baixa do protocolo ARDSnet para aumentar o número de dias sem ventilador em 28 dias em pacientes com síndrome do desconforto respiratório agudo moderada a grave. Aqui, descrevemos a justificativa, o desenho e o status do estudo.

Brazilian version of the Clinical COPD Questionnaire, administered by interview: reliability and validity measurement properties.

OBJECTIVE: To test the reliability, validity, and interpretability of the Brazilian version of the Clinical COPD Questionnaire (CCQ) in patients with COPD. METHODS: Fifty patients with COPD completed the CCQ by interview on two occasions. At the first visit, the CCQ was administered twice, by two different raters, approximately 10 min apart; the patients also underwent spirometry and were administered the COPD Assessment Test, the modified Medical Research Council scale, and Saint George's Respiratory Questionnaire (SGRQ). At the second visit (1-2 weeks later), the CCQ was readministered. We tested the hypothesis that the CCQ total score would correlate positively with the total and domain SGRQ scores (r ≥ 0.5). RESULTS: Of the 50 patients, 30 (60%) were male. The mean age was 66 ± 8 years, and the mean FEV1 was 44.7 ± 17.9% of the predicted value. For all CCQ items, Cronbach's alpha coefficient (95% CI) was 0.93 (0.91-0.96). To analyze the interrater reliability and test-retest reliability of the CCQ, we calculated the two-way mixed effects model/single measure type intraclass correlation coefficient (0.97 [95% CI: 0.95-0.98] and 0.92 [95% CI: 0.86-0.95], respectively); the agreement standard error of measurement (0.65 for both); the smallest detectable change at the individual level (1.81 and 1.80, respectively) and group level (0.26 and 0.25, respectively); and the limits of agreement (-0.58 to 0.82 and -1.14 to 1.33, respectively). The CCQ total score correlated positively with all SGRQ scores (r ≥ 0.70 for all). CONCLUSIONS: The Brazilian version of the CCQ showed an indeterminate measurement error, as well as satisfactory interrater/test-retest reliability and construct validity.

Brazilian version of the Clinical COPD Questionnaire, administered by interview: reliability and validity measurement properties / Versão brasileira do Clinical COPD Questionnaire, aplicado por meio de entrevista: propriedades de medida de confiabilidade e validade

ABSTRACT Objective: To test the reliability, validity, and interpretability of the Brazilian version of the Clinical COPD Questionnaire (CCQ) in patients with COPD. Methods: Fifty patients with COPD completed the CCQ by interview on two occasions. At the first visit, the CCQ was administered twice, by two different raters, approximately 10 min apart; the patients also underwent spirometry and were administered the COPD Assessment Test, the modified Medical Research Council scale, and Saint George's Respiratory Questionnaire (SGRQ). At the second visit (1-2 weeks later), the CCQ was readministered. We tested the hypothesis that the CCQ total score would correlate positively with the total and domain SGRQ scores (r ≥ 0.5). Results: Of the 50 patients, 30 (60%) were male. The mean age was 66 ± 8 years, and the mean FEV1 was 44.7 ± 17.9% of the predicted value. For all CCQ items, Cronbach's alpha coefficient (95% CI) was 0.93 (0.91-0.96). To analyze the interrater reliability and test-retest reliability of the CCQ, we calculated the two-way mixed effects model/single measure type intraclass correlation coefficient (0.97 [95% CI: 0.95-0.98] and 0.92 [95% CI: 0.86-0.95], respectively); the agreement standard error of measurement (0.65 for both); the smallest detectable change at the individual level (1.81 and 1.80, respectively) and group level (0.26 and 0.25, respectively); and the limits of agreement (−0.58 to 0.82 and −1.14 to 1.33, respectively). The CCQ total score correlated positively with all SGRQ scores (r ≥ 0.70 for all). Conclusions: The Brazilian version of the CCQ showed an indeterminate measurement error, as well as satisfactory interrater/test-retest reliability and construct validity.

RESUMO Objetivo: Testar a confiabilidade, validade e interpretabilidade da versão brasileira do Clinical COPD Questionnaire (CCQ) em pacientes com DPOC. Métodos: Cinquenta pacientes com DPOC preencheram o CCQ por meio de entrevista em duas ocasiões. Na primeira visita, o CCQ foi aplicado duas vezes, por dois avaliadores, com intervalo de aproximadamente 10 min; os pacientes também foram submetidos a espirometria e aplicação do COPD Assessment Test, da escala modificada do Medical Research Council e do Saint George's Respiratory Questionnaire (SGRQ). Na segunda visita (1-2 semanas depois), o CCQ foi reaplicado. Testamos a hipótese de que a pontuação total no CCQ se correlacionaria positivamente com a pontuação total e a pontuação nos domínios do SGRQ (r ≥ 0,5). Resultados: Dos 50 pacientes, 30 (60%) eram do sexo masculino. A média de idade foi de 66 ± 8 anos, e a média do VEF1 foi de 44,7 ± 17,9% do valor previsto. Para todos os itens do CCQ, o coeficiente alfa de Cronbach (IC95%) foi de 0,93 (0,91-0,96). Para analisar a confiabilidade interavaliadores e teste-reteste do CCQ, calculamos o coeficiente de correlação intraclasse de duas vias modelo de efeitos mistos para medidas únicas (0,97 [IC95%: 0,95-0,98] e 0,92 [IC95%: 0,86-0,95], respectivamente); erro-padrão de medida do tipo concordância (0,65 para ambas); a mínima mudança detectável individual (1,81 e 1,80, respectivamente) e no grupo (0,26 e 0,25, respectivamente); e os limites de concordância (−0,58 a 0,82 e −1,14 a 1,33, respectivamente). A pontuação total no CCQ correlacionou-se positivamente com todas as pontuações no SGRQ (r ≥ 0,70 para todas). Conclusões: A versão brasileira do CCQ apresentou erro de medida indeterminado, assim como confiabilidade interavaliadores/teste-reteste e validade de construto satisfatórias.

The Brazilian Portuguese-language version of the Manchester Respiratory Activities of Daily Living questionnaire: construct validity, reliability, and measurement error.

OBJECTIVE: To test the construct validity, reliability, and measurement error of the Brazilian Portuguese-language version of the Manchester Respiratory Activities of Daily Living (MRADL) questionnaire in patients with COPD. METHODS: We evaluated 50 patients with COPD, among whom 30 were men, the mean age was 64 ± 8 years, and the median FEV1 as a percentage of the predicted value (FEV1%predicted) was 38.4% (interquartile range, 29.1-57.4%). Pulmonary function and limitations in activities of daily living (ADLs) were assessed by spirometry and by face-to-face application of the MRADL, respectively. For the construct validity analysis, we tested the hypothesis that the total MRADL score would show moderate correlations with spirometric parameters. We analyzed inter-rater reliability, test-retest reliability, inter-rater measurement error, and test-retest measurement error. RESULTS: The total MRADL score showed moderate correlations with the FEV1/FVC ratio, FEV1 in liters, FEV1%predicted, and FVC%predicted, all of the correlations being statistically significant (r = 0.34, r = 0.31, r = 0.42, and r = 0.38, respectively; p < 0.05 for all). For the reliability and measurement error of the total MRADL score, we obtained the following inter-rater and test-retest values, respectively: two-way mixed-effects model intraclass correlation coefficient for single measures, 0.92 (95% CI: 0.87-0.96) and 0.89 (95% CI: 0.81-0.93); agreement standard error of measurement, 1.03 and 0.97; smallest detectable change at the individual level, 2.86 and 2.69; smallest detectable change at the group level, 0.40 and 0.38; and limits of agreement, -2.24 to 1.96 and -2.65 to 2.69. CONCLUSIONS: In patients with COPD in Brazil, this version of the MRADL shows satisfactory construct validity, satisfactory inter-rater/test-retest reliability, and indeterminate inter-rater/test-retest measurement error.

The Brazilian Portuguese-language version of the Manchester Respiratory Activities of Daily Living questionnaire: construct validity, reliability, and measurement error / Versão em português do Brasil do questionário Manchester Respiratory Activities of Daily Living: validade de construto, confiabilidade e erro de medida

ABSTRACT Objective: To test the construct validity, reliability, and measurement error of the Brazilian Portuguese-language version of the Manchester Respiratory Activities of Daily Living (MRADL) questionnaire in patients with COPD. Methods: We evaluated 50 patients with COPD, among whom 30 were men, the mean age was 64 ± 8 years, and the median FEV1 as a percentage of the predicted value (FEV1%predicted) was 38.4% (interquartile range, 29.1-57.4%). Pulmonary function and limitations in activities of daily living (ADLs) were assessed by spirometry and by face-to-face application of the MRADL, respectively. For the construct validity analysis, we tested the hypothesis that the total MRADL score would show moderate correlations with spirometric parameters. We analyzed inter-rater reliability, test-retest reliability, inter-rater measurement error, and test-retest measurement error. Results: The total MRADL score showed moderate correlations with the FEV1/FVC ratio, FEV1 in liters, FEV1%predicted, and FVC%predicted, all of the correlations being statistically significant (r = 0.34, r = 0.31, r = 0.42, and r = 0.38, respectively; p < 0.05 for all). For the reliability and measurement error of the total MRADL score, we obtained the following inter-rater and test-retest values, respectively: two-way mixed-effects model intraclass correlation coefficient for single measures, 0.92 (95% CI: 0.87-0.96) and 0.89 (95% CI: 0.81-0.93); agreement standard error of measurement, 1.03 and 0.97; smallest detectable change at the individual level, 2.86 and 2.69; smallest detectable change at the group level, 0.40 and 0.38; and limits of agreement, −2.24 to 1.96 and −2.65 to 2.69. Conclusions: In patients with COPD in Brazil, this version of the MRADL shows satisfactory construct validity, satisfactory inter-rater/test-retest reliability, and indeterminate inter-rater/test-retest measurement error.

RESUMO Objetivo: Testar a validade de construto, a confiabilidade e o erro de medida da versão em português do Brasil do questionário Manchester Respiratory Activities of Daily Living (MRADL) em pacientes com DPOC. Métodos: Avaliamos 50 pacientes com DPOC, 30 dos quais eram homens. A média de idade foi de 64 ± 8 anos, e a mediana do VEF1 em porcentagem do previsto (VEF1%previsto) foi de 38,4% (intervalo interquartil: 29,1-57,4%). A função pulmonar e limitações experimentadas durante a realização de atividades cotidianas foram avaliadas por meio de espirometria e da aplicação presencial do MRADL, respectivamente. Para a análise de validade de construto, testamos a hipótese de que haveria correlações moderadas entre a pontuação total no MRADL e parâmetros espirométricos. Analisamos a confiabilidade e o erro de medida entre avaliadores e entre teste e reteste. Resultados: Houve correlações moderadas e estatisticamente significativas entre a pontuação total no MRADL e VEF1/CVF, VEF1 em litros, VEF1%previsto e CVF%previsto (r = 0,34, r = 0,31, r = 0,42 e r = 0,38, respectivamente; p < 0,05 para todas). No tocante à confiabilidade e ao erro de medida para a pontuação total no MRADL entre avaliadores e entre teste e reteste, respectivamente, foram obtidos os seguintes valores: coeficiente de correlação intraclasse de duas vias e efeitos mistos para medidas únicas = 0,92 (IC95%: 0,87-0,96) e 0,89 (IC95%: 0,81-0,93); erro-padrão de medida do tipo concordância = 1,03 e 0,97; mínima mudança detectável no indivíduo = 2,86 e 2,69; mínima mudança detectável no grupo = 0,40 e 0,38; limites de concordância = −2,24 a 1,96 e −2,65 a 2,69. Conclusões: Em pacientes com DPOC, a versão brasileira do MRADL apresenta validade de construto satisfatória, confiabilidade interavaliadores/teste-reteste satisfatória e erro de medida interavaliadores/teste-reteste indeterminado.

Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma.

Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodelling. Cannabidiol (CBD) is known to exert immunomodulatory effects through the activation of cannabinoid-1 and - 2 (CB1 and CB2) receptors located in the central nervous system and immune cells, respectively. However, as the role of CBD on airway remodelling and the mechanisms of CB1 and CB2 aren't fully elucidated, this study was designed to evaluate the effects of cannabidiol in this scenario. Allergic asthma was induced in Balb/c mice exposed to ovalbumin, and respiratory mechanics, collagen fibre content in airway and alveolar septa, cytokine levels, and CB1 and CB2 expression were determined. Moreover, expressions of CB1 and CB2 in induced sputum of asthmatic individuals and their correlation with airway inflammation and lung function were also evaluated. CBD treatment, regardless of dosage, decreased airway hyperresponsiveness, whereas static lung elastance only reduced with high dose. These outcomes were accompanied by decreases in collagen fibre content in both airway and alveolar septa and the expression of markers associated with inflammation in the bronchoalveolar lavage fluid and lung homogenate. There was a significant and inverse correlation between CB1 levels and lung function in asthmatic patients. CBD treatment decreased the inflammatory and remodelling processes in the model of allergic asthma. The mechanisms of action appear to be mediated by CB1/CB2 signalling, but these receptors may act differently on lung inflammation and remodelling.